This proposal is for a renewal of the TrialNet Clinical Center at Yale University. The Center was established in 2006. In the previous funding period, 8 new affiliates were added and 2 sites that were not productive discontinued their affiliation. The new affiliates were positioned in and near major metropolitan sites (Chicago, Milwaukee, Providence, New York) and two additional sites are currently being enrolled. The Center has been involved in the TN-01 screening study as well as intervention studies by TrialNet and other collaborating consortia. The Center director has been the PI of the Comparative study.... and the TN-10 Anti-CD3 mAb prevention trial, as well as the ITN027AI (AbATE) and ITN819AI (Treg) trials in the ITN. The Center also was one of the sties able to perform the DirectNet/TrialNet Metabolic Control study. In addition to the direct clinical trial activities, th Center investigators have supported the TrialNet mission in mechanistic studies and leadership roles. Two significant challenges for TrialNet prevention studies are identified and will be addressed with ongoing and new studies. One of these is to identify which and when at-risk subjects are progressing to diabetes. The other is to determine which subjects are most likely to respond to therapies. Studies that address these questions would help to design more efficient trials that require fewer subjects, are shorter in duration, and have a lower risk:benefi ratios than trials that involve unselected individuals. In addition, these and other proposed studies may help in the selection of combinations of agents to be tested in prevention trials. The TrialNet investigators will continue studies of samples from and subjects in TrialNet studies to help with the development of these biomarkers. In the next funding period, we propose to enhance recruitment into TrialNet studies using novel methods that take advantage of the electronic medical record (Epic) that is used by most of our affiliates and advertisement with electronic media. With these tools, we will be able to identify patients whose family may be interested in TrialNet prevention studies but whom may not be familiar with TrialNet because they do not attend an endocrinologist who is involved in the consortium. Our approach will involve direct patient communications using Best Practices, My Chart, and registries that are created by Epic. In addition, we plan to also provide direct communication to subjects through an expanded use of media such as Yahoo and others that have already shown potential to increase trial related interest. The past funding period has shown substantial growth in the activities at the Yale site. Our plan to expand this work in the next funding period by using innovative technologies, continuing our enlistment of affiliates in areas of dense populations in the Northeast that are underserved, while maintaining our studies to improve the quality and efficiency of TrialNet trials.